Amido and amino triazolo benzodiazepines

ABSTRACT

WHEREIN R1, R2, R3, R4, and R5 are defined as above and R is alkyl of one to three carbon atoms, inclusive.   WHEREIN R&#39;&#39; and R&#39;&#39;&#39;&#39; are hydrogen, alkyl of one to three carbon atoms, inclusive, or together   Compounds of the formula:

United States Patent [1 1 Hester, J r.

[ AMlDO AND AMINO TRIAZOLO BENZODIAZEPINES Jackson B. Hester, Jr.,Galesburg, Mich.

The Upjohn Company, Kalamazoo, Mich.

221 Filed: Apr. 28, 1971 [21] Appl. No.: 138,287

[75] Inventor:

[73] Assignee:

[52] U.S. Cl 260/308 R, 71/92, 260/247.1, 260/247.2 A, 260/2475 B,260/293.59,

[51] Int. Cl. C07d 57/02, C07d 99/02 [58] Field of Search 260/308 R,247.1, 260/2475 B, 293.59, 247.2 B

[56] References Cited OTHER PUBLICATIONS Houben-Weyl, Methoden DerOrganischen Chemie, Vol. 11/2, (Stuttgart, 1958), pages 20-23.

Primary Examiner-Alton D. Rollins Attorneyl-lans L. Berneis and JohnKekich [57] ABSTRACT Compounds of the formula:

[ Sept. 18, 1973 wherein R and R" are hydrogen, alkyl of one to threecarbon atoms, inclusive, or together are pyrrolidino, piperidino, hexamet hyleneimino, or morpholino; wherein R' is wherein R R R R and Rare defined as above and R is alkyl of one to three carbon atoms,inclusive.

3 Claims, No Drawings AMIDO AND AMINO TRIAZOLO BENZODIAZEPINES The newcompounds of formula V above and the pharmacologically acceptable acidaddition salts thereof have oral and parenteral sedative andtranquilizing activity and can be employed for tranquilizing mammalse.g. pets and 200 animals in transit.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention isdirected to novel organic compounds and is more specifically concernedwith amidoand amino-triazolobenzodiazepines of the formulae below and amethod of the production thereof.

The novel compounds and the process therefor can be illustrativelyrepresented as follows:

wherein R and R" are hydrogen, alkyl of one to three carbon atoms,inclusive, or together are pyrrolidino, piperidino, hexamethyleneimino,and morpholino; wherein R is hydrogen or alkyl defined as above; andwherein R R R and R are selected from the group consisting of hydrogen,alkyl defined as above, halogen, nitro, cyano, trifluoromethyl, andalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, inwhich the carbon chain moiety is of one to three carbon atoms,inciusive.

The process of this invention comprises treating an ester of formula Iwith ammonia or an amine at a temperature between 2S-200 C. in anorganic solvent to obtain an amide of formula II; reducing the amidewith borane or a metal aluminum hydride in a solvent between roomtemperature and the reflux temperature of mula above and oxidizing IlIeg. with manganese dioxide, ruthenium tetroxide or with diethylazodicarboxylate to obtain the benzodiazepine of formula VI.

The active compounds of this invention II, III, and IV can be summarilyrepresented by Formula V wherein R and R are hydrogen, alkyl of one tothree carbon atoms, inclusive or together R5 n Rt are pyrrolidino,piperidino, hexamethylenemino, and

R morpholino; wherein R' is III the reaction mixture to obtain the amineIII of the for- F DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkylgroups of one to three carbon atoms, inclusive, are exemplified bymethyl, ethyl, propyl, and isopropyl.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, dialkylamino which is of one to three carbon atoms,inclusive, is defined as lower-alkyl of one to three carbom atoms,inclusive, as above.

The term halogen includes fluorine, chlorine, and bromine.

The novel compounds of the formula V(or II, III, and IV) includingpharmacologically acceptable acid addition salts thereof, have sedative,tranquilizing and muscle relaxant effects in mammals and birds.

The pharmacologically acceptable acid addition salts of compounds offormula -V (or II, III, and IV) contemplated in this invention, are thehydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates,cyclohexanesulfamates, methanesulfonates and the like, prepared byreacting a compound of formula II, III, or IV with an excess of theselected pharmacologically acceptable acid.

Sedative effects of N,N-dimethyl-8-chloro-6-phenyl-4I-I-s-triazolo[4,3-a][ l ,4]benzodiazepinel -acetamide are shown by thefollowing tests in mice:

CHIMNEY TEST Med. Exp. 4, [145 (1961)]: The effective intraperitonealdosage for 50 percent of mice (ED:,,,) is 8.8 mg./kg. The testdetermines the ability of mice to back up and out of a vertical glasscylinder within 30 seconds. At the effective dosage, 50 percent of themice failed doing it.

DISI-I TEST Mice in Petri dishes (IO cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED equals the dose of test compound at which 50 percentof the mice remain in the dish. The ED (intraperitoneal administration)in this test was 7.0 mgJkg.

PEDESTAL TEST The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than one minute.The ED (intraperitoneal administration) is 12.5 mg./kg.

NICOTINE ANTAGONISM Mice in a group of 6 are injected with the testcompound N ,N-dimethyl-8-chloro-6-phenyl-4l-I-striazolo[4,3-a][1,4]benzodiazepine- I -acetamide. 30 minutes later the mice includingcontrol (untreated) mice are injected with nicotine salicylate (2mg./kg.). The control mice show overstimulation, i.e., (1) runningconvulsions followed by (2) tonic extensor fits, followed by (3) death.An intraperitoneal dosage of 1.6 mg./kg. of the test compound protected50 percent of the mice against (2) and 1.8 mg./kg. against (3).

The pharmaceutical forms of compound V (or II, III, and IV) contemplatedby this invention include pharmaceutical compositions suited for oral,parenteral and rectal use, e.g., tablets, powder packets, cachets,dragees, capsules, solutions, suspensions, sterile injectable forms,suppositories, bougies, and the like. Suitable diluents or carriers suchas carbohydrates (lactose), proteins, lipids, calcium phosphate,cornstarch, stearic acid, methylcellulose and the like may be used ascarriers or for coating purposes. Oils, e.g. coconut oil, sesame oil,safflower oil, cottonseed oil, peanut oil may be used for preparingsolutions or suspensions of the active drug. Sweetening, coloring andflavoring agents may be added.

For mammals and birds food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

As tranquilizer the compounds of formula V can be used in dosages ofl-20 mg./kg. in oral or injectable preparations as described above, toalleviate tension and anxiety in mammals, or birds, such as e.g., occurswhen animals are shipped.

Other acid addition salts of the compounds of formula V can be made,such as the fluosilicic acid addition salts which are usefulmothproofing compounds or the trichloroacetates useful as herbicidesagainst Johnson grass, Bermuda grass, yellow foxtail, and green foxtail,and quack grass.

The starting materials of formula I of this invention, substituted orunsubstituted 6-phenyl-4H -striazolo[4,3-a] 1,4]benzodiazepinel aceticacid methyl esters are produced from 6-phenyl-4H-striazolo[4,3-a]-[ l,4]benzodiazepinel-acetonitriles as shown in Preparation 2. Theacetonitriles are produced as in preparation 1 froml,3-dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-thiones [described by G.A. Archer et al., J. Org. Chem. 29, (231) 1964].

In carrying out the process of this invention a compound of formula I isreacted with aqueous ammonia or aqueous lower dialkylamine indimethylformamide, dioxane, tetrahydrofuran or the like or with adialkylamine, or an lower N-heterocyclicamine, preferably in a solvent,e.g. dimethylformamide, dimethylacetamide or the like, between 25-200 C.The N- heterocyclicamines useful for these are piperidine, pyrrolidine,morpholine, hexamethyleneimine.

The product (II) obtained is recovered and purified by standard methodse.g. extraction, chromatography, and crystallization.

Compound II, in ether or tetrahydrofuran when treated with borane (B l-lor lithium aluminum hydride between 2580 C. yields the amine of formulaIII which is recovered and purified by conventional means e.g.extraction, chromatography, and recrystallization.

Compound III can be oxidized in part with active manganese dioxidepreferably in benzene, tetrahydrofuran or other anhydrous solvent orwith ruthenium tetroxide in a solvent such as chloroform orcarbontetrachloride.

Instead of manganese dioxide or ruthenium tetroxide diethylazodicarboxylate is useful and is preferred. The temperature of thisreaction is between 25-80 C. and the time is between 1 and 18 hours. Theproduct IV is isolated and purified by conventional means e.g.extraction, chromatography, and recrystallization.

The following Preparations and examples are illustrative of theprocesses and products of the present invention, but are not to becontrued as limiting.

PREPARATION l 8-Chloro-6-phenyl-4I-I-s-triazolo[4,3-a]- l,4]benzodiazepinel -acetonitrile A mixture of1,3-dihydro-7-chloro-5-phenyl-2H-l ,4- benzodiazepine-Z-thione (5.72 g.,0.02 mole), cyanoacetic acid hydrazide (5.95 g., 0.06 mole) andnbutylalcohol (275 ml.) was refluxed for 7.5 hours with a slow stream ofnitrogen bubbling through the mixture. The mixture was then concentratedin vacuo. The resulting residue was suspended in water and extractedwith methylene chloride. The extract was dried and concentrated. Theresidue was chromatographed on silica gel (400 g.) with 2 percentmethanol-98 percent CHCl The product eluted from the column wascrystallized from ethyl acetate-Skelly B hexanes to give 2.62 g. of8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-l-acetonitrile of melting point l98-201 C. Anal.calcd. for C ll ClN z C, 64.77; H, 3.63; c1, 10.62.

Found: C, 64.52; H, 3.86; Cl, 10.51.

PREPARATION 2 8-Chloro-6-pheny1-4l-I-s-triazolo[4,3-a]-[1,4]benzodiazepine-l-acetic acid methyl ester A stirred mixture of8-chloro-6-phenyl-4H-striazolo[4,3-a][ 1 ,4]benzodiazepinel-acetonitrile (1.00 g., 0.003 mole), methanol (2 ml.) and ether (6 ml.)was cooled in a salt-ice bath and saturated with a stream of anhydroushydrogen chloride during minutes. The mixture was allowed to warm slowlyto ambient temperature and stand for 18 hours; it was then poured intowater. This mixture was neutralized with sodium bicarbonate andextracted with chloroform. The extract was washed with brine, dried overanhydrous magnesium sulfate and then concentrated. The residue wascyrstallized from methanol to give 0.149 g. of a by-product of meltingpoint 184.5-188 C. (d). The mother liquor was crystallized frommethanolethyl acetate to give 0.126 g. of a by-product of melting point205.5-207.5 (d.) C. The motherliquor from this crystallization wasconcentrated and chromatographed on silica gel (50 g.) with 2 percentmethanol- 98 percent chloroform. The first compound eluted from thecolumn was crystallized from methanol-ethyl acetate to give 0.169 g. ofmelting point 202.5-203.5 C. (d.) and 0.125 g. of melting point200.5202.5 C. (d.) of 8-chloro-6-phenyl-4l-l-s-triazolo 4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester. The analytical samplehad a melting point of 202203 C.

ANAL. CALCD. FOR C, H, -,ClN O- C, 62.21; H, 4.12; Cl, 9.67; N, 15.28.Found:

C, 62.32; H, 4.14; Cl, 10.15; N, 15.33.

EXAMPLE 1 N,N-dimethyl-8-chloro-6-phenyl-4l-l-s-triazolo-[4,3- a] l ,4]benzodiazepine- 1 -acetamide A suspension of8-chloro-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine-l-aceticacid methyl ester (0.367 g., 0.001 mole) in percent aqueousdimethylamine (5 ml.) and dimethylformamide (6 ml.) was treated withdimethylamine hydrochloride (81.5 mg.) and stirred under nitrogen atambient (2325 C.) temperature for 18 hours. It was poured into coldwater, saturated with sodium chloride and extracted with methylenedichloride. The extract was washed with a dilute sodium chloridesolution, dried over anhydrous potassium carbonate and concentrated invacuo. The resulting residue was washed successively with xylene andtoluene with'concentrating after each addition. The resulting materialwas crystallized from methanolethyl acetate to give 0.173 g. ofN,N-dimethyl-8- chloro-6-phenyl-4l-l-s-triazolo[4,3-a][1,4]benzodiazepine-l-acetamide of melting point 204-205.5 C.

ANAL. CALCD. FOR C l-l ClN C, 63.24; H, 4.78; CI, 9.35; N, 18.44 Found:

C, 63.01; H, 4.83; Cl, 9.39; N, 18.41.

EXAMPLE 2 N,N-Dimethyl-8-chloro--(o-chlorophenyl)-4l-I-striazolo[4,3-a][1,4]benzodiazepinel -acetamide In the manner given in Example 1,8-chloro6-(ochlorophenyl)-4H-s-triazolo[ 4,3-a][1,4]benzodiazepine-l-acetic acid methyl ester was reacted withdimethylamine in dimethylformamide to give N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-striazolo[4,3-a][ 1,4]benzodiazepine-1-acetamide.

EXAMPLE 3 N,N-dimethyl-8-chloro-6-(2,6-dichlorophenyl)- 4H-s-triazolo[4,3-a][ 1 ,4lbenzodiazepine-1-acetamide In the manner givenin Example 1, 8-chloro-6-(2,6- dichlorophenyl )-4I-I-s-triazolo[4,3-a][l ,4lbenzodiazepine-l-acetic acid methyl ester was reacted withdimethylamine in dirnethyl formamide to give N,N- dimethyl-8-chloro-6-(2,6-dichlorophenyl )-4I-1-striazo1o[4,3-a][ 1,4]benzodiazepinel-acetamide.

EXAMPLE 4 N,N-Dimethyl-8-chloro-6-(2,6-difluorophenyl)-4l-I-s-triazolo[4,3-a][ l ,4]benzodiazepine-1-acetamide In the manner givenin Example 1, 8-chloro-6-(2,6- difluorophenyl)-4H-s-triazolo[4,3-a][ l,4]benzodiazepine-l-acetic acid methyl ester was reacted withdimethylamine in dimethylformamide to give N,N-dimethyl-8-chloro-6-(2,6-difluorophenyl)-4l-I-striazolo[4,3-a][ 1,4lbenzodiazepine-1 -acetamide.

EXAMPLE 5 N,N-Tetramethylene-4-rnethyl-8-nitro-6-(mbromophenyl)-4H-s-triazolo[4,3-a][ 1 ,4]benzodiazepinel -acetamide 1n the mannergiven in Example 1, 4-methyl-8-nitro-6(m-bromophenyl)-4I-I-s-triazolo[4,3-

a][1,4]benzodiazepine-l-acetic acid ethyl ester was re- EXAMPLE 7N,N-Hexamethylene-10-isopropyl-6-(pmethylthiophenyl)-4l-1-s-triazolo[4,3-a] l ,4]benzodiazepinel -acetamide In the manner given in Example 1,l0-isopropyl-6-(pmethylthiophenyl)-4H-s-triazolo[4,3- a][1,4]benzodiazepine- 1 -acetic acid ethyl ester was reacted withhexamethyleneimine in dimethylformamide to give N,N-hexamethy1ene-isopropyl-6-(pmethylthiophenyl)-4H-s-triazo1o[4,3-a1- 1,4lbenzodiazepinel -acetamide.

EXAMPLE 8 4-[[9-dipropy1amino-8-ethylsulfony1-6-(pmethoxyphenyl)-4l-l-s-triazolo[4,3-a][ 1 ,4]benzodiazepine-1-yl] acetyl ]morpholine In the manner given inExample 1, 9-dipropylamino-8-ethylsu1fonyl-6-(p-methoxypheny1)-4l-l-striazo1o[4,3-a]-[1,4]benzodiazepine-l-aceticacid propyl ester was reacted with morpholine in dimethylformamide togive 4-[[9-dipropy1amino-8-ethy1su1fony1-7-(p-methoxyphenyl)-4H-s-triazo1o{4,3- a] l,4]benzodiazepine-1-yl]acetyl]morpho1ine.

EXAMPLE 9 N,N-Dipropy1-9-ethylsulfiny1-6-(m-nitropheny1)-4H-s-triazo1o[4,3-a][ 1 ,4]benzodiazepine- 1 -acetamide In the manner givenin Example 1, 9-ethy1sulfiny1-6- (m-nitrophenyl)-4H-s-triazo1o[4,3-a][1,4]benzodiazepine-l-acetic acid ethyl ester was reacted withdipropylamine in dimethylformamide to give N,N-dipropyl-9-ethyIsulfinyl-6-(m-nitrophenyl)-4H-striazolo[4,3-a][1,4]benzodiazepine-l-acetamide.

EXAMPLE 1O 7 ,S-Dicyano-10-fluoro-6-(p-isopropylsulfonyl)-phenyl)-4H-s-triazo1o[4,3-a][1,4]benzodiazepine-1- acetamide In themanner given in Example 1, 7,8-dicyano-10-fluoro-(p-isopropylsulfonylphenyl)-4H-s-triazo1o[4,3-a]-[1,4]benzodiazepine-l-acetic acid methyl ester was reacted withaqueous ammonium hydroxide in dioxane to give7,8-dicyano-10-f1uoro-6-(pisopropylsulfonylphenyl)-4l-l-s-triazo1o[4,3-a][1,4]benzodiazepine-1-acetamide.

EXAMPLE 1 lN,N-DimethylJ-bromo-8-diethylamino-6-(mcyanophenyl)-4H-s-triazo1o[4,3-a][1,4]benzodiazepine-1 -acetmide 1n the manner given in Example 1, 7-bromo-8-diethylamino-6-(m-cyanophenyl)-4H-s-triazolo[4,3-a][1,4lbenzodiazepine-1-acetic acid methyl ester was reacted withdimethylamine in dimethylformamide to giveN,N-dimethyl-7-bromo-8-diethylamino-6-(mcyanophenyl)-4H-s-triazolo-[4,3-a1[1,4]benzodiazepine-l-acetamide.

EXAMPLE 12 N,N-Dimethyl-4-propy1-8-bromo-6-(obromophenyl)-4H-s-triazo1o[4,3-a][ 1,4]benzodiazepine- 1 -acetamide In the mannergiven in Example 1, 4-propy1-8-bromo-6-(o-bromopheny1)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester was reacted withdimethylamine in dimethylformamide to giveN,N-dimethy1-4-propyl-8-bromo-6-(obromophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine-l-acetamide.

EXAMPLE 13 1-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6-phenyl-4l-l-s-triazo1o[4,3-a][1,4]benzodiazepine A solution of 1.5 g. ofN,N-dimethy1-8-chloro-6- pheny1-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine-1- acetamide was slowly added to a solution of boranein tetrahvdrofuran. The reaction mixture was heated to 40 C. and waskept at this temperature for 15 hours. The mixture was then evaporatedin vacuo and the remaining residue was suspended in water and extractedwith chloroform. The chloroform extract was dried over anhydrouspotassium carbonate, then evaporated to dryness and the residuerecrystallized twice from ethyl acetate, providing1-[Z-(dimethylamino)ethyl]-8- chloro-S ,6-dihydro-6-phenyL4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

EXAMPLE l4 1- 2-( dimethylamino )ethyl ]-8-chloro-5 ,6-dihydro-6-(o-chlorophenyl)-4l-l-s-triazolo[4,3- a][1,4]benzodiazepine 1n themanner given in Example 13, N,N-dimethy1-8-ch1oro-6-(o-chlorophenyl)-4l-l-s-triazo1o[4,3-a][1,4]benzodiazepine-l-acetamide was reduced with borane to give1-[2-(dimethy1amino)ethy1]-8-chloro- 5 ,6-dihydro-6-( o-chlorophenyl)-4H-s-triazo1o 4,3-

a][ 1 ,4]benzodiazepine.

EXAMPLE l5 1-[2-( Dimethylamino )ethyl]-8-chloro-5 ,6-dihydro- 6-(2,6-dich1orophenyl)-4l-l-s-triazolo[4,3- a] 1 ,4]benzodiazepine 1n themanner given in Example 13, N,N-dimethy1-8-chloro-6-(2,6-dichloropheny1)-4H-s-triazo1o[4,3-a][1,4]-benzodiazepine-1-acetamide was reduced with borane to give1-[2-dimethylamino)ethyl]-8-chloro- 5 ,6-dihydro-6-( 2,6-dichloropheny1)-4l-l-s-triazolo[4 ,3 a][ 1,4]benzodiazepine.

EXAMPLE l6 1-[2-(Diethy1amino)ethy1l-8-chloro-5,6-dihydro-6-difluorophenyl )-4H-s-tria2o1o 4 ,3 a][ 1,4]benzodiazepine In the mannergiven in Example 13, N,N-diethy1-8-ch1oro-(2,6-difluorophenyl)-4l-l-s-triazo1o[4,3-a][1,4]benzodiazepine-1-acetamide was reduced with borane to give1-[2-(diethylamino)ethyl]-8-ch1oro-5,6-dihydro-6-(2,6-difluorophenyl)-4l-l-s-triazo1o[4,3- a]1,4]benzodiazepine.

EXAMPLE 19 l-[2-( Hexamethyleneimino )ethyl l O-isopropyl-S ,6-dihydro-6-( p-methylthiophenyl )-4H-s-triazo1o 4,3-a l 1.4lbenzodiazeoine In the manner given in Examplehexamethleneiminol-isopropyl-6-(pmethylthiophenyl)-4H-s-triazolo[4,3-a]- [l,4]benzodiazepine-l-acetamidewas reduced with borane to give l-[2-(hexamethyleneimino)ethyll-10-triazolo[4,3-a][ 1,4]-benzodiazepine.

EXAMPLE l-( 2-m orpholinoethyl )-8-ethylsulfonyl-5 ,6-dihydro-6-(p-methyoxyphenyl)-4l-I-s-triazoIo[4,3-a][ l ,4]-

' benzodiazepine In the manner given in Example 13, 4-[[8-ethylsulfonyl-6-(p-methyoxyphenyl)-4I-I-striazoIo[4,3-a][ I,4]benzodiazepin- 1 yl]acetyl]morpholine was reduced with borane to give1 2-morpholinoethyl )-8-ethylsulfonyl-5 ,6-dihydro-6-(p-methoxphenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

EXAMPLE 21 1-[ 2-( Dipropylamino )ethyl1-9-ethylsulfinyl-5 ,6-dihydro-6-(m-nitrophenyl)-4I-I-s-triazolo[4,3a][ 1,4]-

benzodiazepine In the manner given in Example 13, N,N-dipropyl-9-ethylsulfinyl-6-( m-nitrophenyl)-4H-s-triazolo[4,3- a][ 1,4]-benzodiazepine-l-acetamide was reduced with borane to givel-[2-(dipropylamino)ethyl]-9-ethylsulfir'ryl-S,6-dihydro-6-(m-nitrophenyl)-4l-I-striazolo[4,3-a][1,4]benzodiazepine.

' EXAMPLE 22 V l-[ Z-(dimethylamino )ethyll-7-bromo-8-(diethylmino)-5,6-dihydro-6-(m-cyanophenyl)-4I-I-striazolo[4,3-a]-[1,4]benzodiazepineIn the manner given in Example 13, N,N-dimethyl-7-bromo-8-(diethylamino)-6-(m-cyanophenyl)-4I-I-striazo-[4,3-a][I,4]benzodiapine-l-acetamidewas reduced with borane to give I-[Z-(dimethylamino )ethyl]-7-bromo-8-(diethylamino)-5,6-dihydro-6-(mcyanophenyl)-4l-I-s-triazolo-[4,3-

a][ 1,4 ]benzodiazepine.

EXAMPLE 23 l-[2-(diethylamino )ethyl]-4-propyl-8-brorn-5 ,6- dihydro-6-(o-bromophenyl)-4H-s-triazolo[4,3a][ 1,4]- benzodiazepine In the mannergiven in Example l3, N,N-diethy1-4-propyI-8-bromo6-(o-bromophenyl)-4H-s-trizaolo[4,3- a][ l,4]-benzodiazepine-l-acetamide was reduced with borane to givel-[2-(diethylamino)ethyl]-4-propyl-8-bromo-S,6-dihydro-6-(o-bromophenyl)-4I-I-striazolo[4,3-a][1,4]benzodiazepine.

EXAMPLE 24 I-[ 2-( Dimethylamino )ethyl]-8-chIoro 6-phenyl-4H-s-triazolo[4,3-a][ l ,4]benzodiazepine' A stirred suspension ofI-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6-phenyI-4l-I-s-triazolo[4,3-a][1,4]-benzodiazepine and diethyl azodicarboxylate in benzene washeated to reflux and kept at this temperature for about 15 hours. Themixture was then cooled and evaporated' The residue was suspended inwater and extracted with chloroform. The chloroform extracts were driedwith anhydrous potassium carbonate, evaporated and the resulting residuetwice crystallized from ethyl acetate to give l-[2-(dimethylmino)ethyl]-8-chloro-6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine.

2 l0 EXAMPLE 2s 1-[Z-(dimethylamino)ethyl1-8-chloro-6-(ochlorophenyl)-4I-I-s-triazolo[4,3-a][ 1,4]benzodiazepine In the manner given in Example 24, a suspensionof l-[2-(dimethylamino)ethyl ]-8-chloro-5 ,6-dihydro-6-(o-chlorophenyl)-4H-s-triazolo[4,3- I a][ 1,4]benzodiazepine wasoxidized with diethyl azodicarboxylate to giveI-[2-(dimethylamino)ethyl1-8-chloro-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3- a][ l,4]benzodiazepine.

EXAMPLE 26 I-[2-(Dimethylamino)ethyI]-8-chIoro-6-( 2,6-dichlorophenyl)-4I-I-s-triazolo[4,3- a][ 1 ,4]benzodiazepine In themanner given in Example 24, a supension of l-2-(dimethylamino)ethyl1-8-chloro-5 ,6-dihydro-6- (2 ,6-dichlorophenyl)-4H-s-triazolo 4,3- a][ 1,4]benzodiazepine was oxidized with diethylazodicarboxylate to give I-[2-(dimethylamino)ethyl]-8- chloro-6-(2,6-dichlorophenyl )-4H-s-triazolo 4 ,3- a][ 1,4]benzodiazepine.

EXAMPLE 27 1- 2-( diethylamino )ethyl -8-chloro-6-( 2,6-difluorophenyl)-4I-I-s-triazolo[4,3- a][ l,4]benzodiazepine In themanner given in Example 24, a suspension ofl-[2-(diethylamino)ethyl]-8-ch1oro-5 ,6-dihydro-6- (2,6-difluorophenyl)-4H-s-triazolo[ 4,3 a][ 1,4]benzodiazepine was oxidized with diethylazodicarboxylate to give l-[2-(diethylamino)ethyl1-8- chIoro-6-(2,6-difluorophenyl )-4I-I-s-triazolo 4,3 a][ I ,4]benzodiazepine.

EXAMPLE 28 1-( 2-Pyrro1idinoethyl )-4-methyl-8-nitro-6-(mbromophenyl)-4H-s-triazolo[4,3- a] 1,4]benzodiazepine In the mannergiven in Example 24, a suspension of l-(2-pyrrolidinoethyl)-4-methyl-8-nitro-5 ,6-dihydro-6-(m-bromophenyl)-4H-s-triazolo[4,3- a][ l,4]benzodiazepine was oxidizedwith diethyl azodicarboxylate to give 1-(2-pyrrolidinoethyl)-4-methyl-8-nitro-6-(m-bromophenyl)-4H-s-triazolo[4,3- a 1,4]benzodiazepine EXAMPLE29 l 2-morpholinoethyl )-7-(diisopropylamino )-5,6-dihydro-6-[p(dipropylamino)phenyl]-4H-striazolo[4,3-a][ 1,4lbenzodiazepine; 1-[Z-piperidinoethyl]-8-chloro-5 ,6-dihydro-6-( 3 ,4-dimethylphenyl)- 4H-s-triazolo[4,3- a] l ,4]benzodiazepine; l-(2-piperidinoethyl)-5 ,6-dihydro-6-(2-methyl-4-methoxyphenyl-4l-l-s-triazolo[4,3- a 1,4 ]benzodiazepine; l-(2-pyrrolidinoethyl)-8-methylthio-5,6-dihydrophenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; l-(2-pyrrolidinoethyl)-8-methoxy-5 ,6-dihydro-6-phenyl-4H-s-triazolo[4,3-1[ 1,4]benzodiazepine; an the like.

in the manner given in Example 24 other 1-(2- aminoethyl) andI-[Z-(substituted amino)ethyl]-5,6- dihydro-6-phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepines (Ill) can be oxidized to give the correspondingl-(2-aminoethyl) and l-[2- (substitutedamino)ethyl]-6-phenyl-4H-s-triazolo-[4,3- a][ 1,4]benzodiazepines offormula IV. Representative compounds, thus obtained, include:l-[2-(diethylamino)ethyl]-l0-chloro-6-(misopropylphenyl)-4H-s-triazolo[4,3-

a][ l ,4 ]benzodiazepine;

1-[Z-(dipropylamino)ethyl]-9-(dipropylamino)-6-[p-(dipropylamino)phenyl]-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine;l-[2-(dimethylamino)ethyl]-8-methylsulfinyl)-6-(onitrophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;l(2-morpholinoethyl)-7-(ethylsulfonyl)-6-(ocyanophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

1-( 2-piperidinoethyl)-4'propyl-6-[m-(methylthio)phenyl]-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepine;

a] l ,4lbenzodiazepine;

l-( 2-pyrrolidinoethyl)-7,9-diethoxy-6-(methoxyphenyl)-4H-s-triazolo[4,3-

a][ l ,41benzodiazepine; l-[2-(diisopropylamino)ethyl]-4-ethyl-6-[o-(ethylthio)-phenyl]-4H-s-tria2olo[4,3-

a][ l ,4lbenzodiazepine;l-[2-(diethylamino)ethyl]-4-methyl-7,l0-dichloro-6-[m-isopropoxyphenyl]-4H-s-triaz0lo[4,3-

a][ l ,4]benzodiazepine;1-[2-(diethylamino)ethyl1-9-(dipropylamino)-6-[m- (propylthio)phenyl]-4H-s-triazolo[4,3-

a] l ,4]benzodiazepine;

1-( 2-morpholinoethyl )-7-( diisopropylamino)-6-[ p-(dipropylamino)phenyl]-4H-s-triazolo[4,3-

a][ l ,4lbenzodiazepine;

l-( Z-piperidinoethyl )-8-chloro-6-( 3 ,4-dimethylphenyl)-4H-s-triazolo[4,3-

a][ l,4]benzodiazepine; 1-( 2-pyrrolidinoethyl )-6-(2-methyl-4-methoxyphcnyl 4H-s-triazolo[4,3-a][ 1,4]benzodiazepine; l2-pyrrolidinoethyl )-8-methylthio-6-phenyl-4H-striazolo-[4,3-a][ l,4]benzodiazepine. 1-( 2-pyrr0lidinoethyl)-8-methoxy-6-phenyl-4H-striazolo-[4,3-a][1,4]benzodiazepine; and thelike.

The pharmacologically acceptable acid addition salts of compounds offormula V can be prepared and isolated by conventional processes, suchas reacting a compound of formula V with a selected pharmacologicallyacceptable acid. Such acids include hydrochloric, hydrobromic,phosphoric, sulfuric, acetic, tartaric, lactic, citric, malic, maleic,methanesulfonic, benzenesulfonic, cyclohexanesulfonic acids, and thelike. The reaction is conveniently performed in an organic solvent e.g.ether, dioxane, tetrahydrofuran and the salts recovered by evaporatingthe solvent.

1 claim:

1. A compound of the formula:

wherein R and R are hydrogen, or alkyl of one to three carbon atoms,inclusive, or together are pyrrolidino, piperidino, hexamethyleneimino,or morpholino; wherein R is hydrogen or alkyl, defined as above; whereinR R R and R are selected from the group consisting of hydrogen, alkyldefined as above halogen, nitro, cyano, trifluoromethyl, and alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, in which thecarbon chain moiety is of one to three carbom atoms, inclusive, and thepharmacologically acceptable acid addition salts thereof.

N,N-dimethyl-8-chloro-6-phenyl-4H-striazolo[4,3-a]-[ l,4]benzodiazepinel -acetamide.

3. N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-striazolo-[ 4,3-a][ l,4]benzodiazepinel -acetamide.

* II! i

2. N,N-dimethyl-8-chloro-6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine-1-acetamide. 3.N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo-(4,3-a)(1,4)benzodiazepine-1-acetamide.